Median follow-up was 30.8 months, 294 deaths were reported during this period. Compared with patients achieving a VO 2peak <0.96 L.min 1 , the adjusted hazard ratio (HR) for all-cause mortality was 0.64 (95% CI, 0.46 to 0.88) for a VO 2peak of 0.961.29 L.min 1 , and 0.56 (95% CI, 0.39 to 0.80) for a VO 2peak of >1.29 L.min 1 (p trend = 0.). The corresponding HRs for resected patients were 0.66 (95% CI, 0.46 to 0.95) and 0.59 (95% CI, 0.40 to 0.89) relative to the lowest VO 2peak category (p trend =0.), respectively. For non-resected patients, the HRs were 0.78 (95% CI, 0.34 to 1.79) and 0.39 (95% CI, 0.16 to 0.94) relative to the lowest category (p trend =0.).
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Using a prospective design, 398 patients with potentially resectable NSCLC enrolled in Cancer and Leukemia Group B (CALGB) were recruited between and . Participants performed a cardiopulmonary exercise test to assess VO 2peak and were observed for death or until June . Cox proportional models were used to estimate the risk of all-cause mortality according to cardiorespiratory fitness category defined by VO 2peak tertiles (<0.96 / 0.961.29 / >1.29 L.min 1 ) with adjustment for age, gender, performance status.
Cardiorespiratory fitness, as measured by an objective exercise tolerance test, reflects the integrative ability of the cardiopulmonary system to deliver adequate oxygen and substrate to metabolically active skeletal muscles for ATP resynthesis. 6 Peak oxygen consumption (VO 2peak ) provides the gold standard (direct) assessment of cardiorespiratory fitness. Direct or estimated measurement of VO 2peak is a well-established independent predictor of mortality in a broad range of non-cancer populations. 7 , 8 Accordingly, formalized exercise tolerance testing can provide powerful prognostic and risk stratification information to clinicians in these populations. In contrast, cardiorespiratory fitness assessment is not used in the oncology setting other than to provide a preoperative functional assessment of pulmonary resection candidates. 5 Nevertheless, these tests may provide prognostic information beyond PS scoring systems currently used in the oncology setting. Here, we investigate the prognostic significance of preoperative VO 2peak on long-term all-cause mortality among operable candidates with NSCLC.
Among the wide spectrum of predictive and prognostic markers that have been identified, performance status (PS) has consistently been demonstrated to be a strong, independent predictor of survival and a central component of practical prognostic models in NSCLC. 3 PS is an assessment of the patients physical functioning and capability of self-care as recorded by oncology health professionals but such scoring systems are subjective and have poor inter-rater reliability. Moreover, these instruments fail to characterize the degree or potential causes of physiologic limitation, assess symptom responses to exertion or inform therapeutic intervention. 5
Lung cancer is the second most commonly diagnosed malignancy among American adults accounting for approximately 15% of all cancer diagnoses. 1 An estimated 80% of lung cancer patients will be diagnosed with non-small cell lung cancer (NSCLC) and ~25% will present with early-stage (operable) disease. 1 NSCLC continues to be the leading cause of cancer-related mortality accounting for ~20% of all deaths. 1 Despite significant advancements in surgical procedures and introduction of postoperative chemotherapy, prognosis remains disappointing with five-year relative survival rates ranging from ~70% for patients with stage I disease to only ~25% for stage IIIA disease. 2 Further, there is considerable survival variability within stage due to the heterogeneous features of disease pathophysiology and broad range of clinical comorbid conditions at presentation. 3 , 4 Thus, identifying accurate markers of prognosis to optimize treatment and survival outcomes in NSCLC is of major clinical importance.
The Cox proportional hazards model was used to examine the impact of preoperative VO 2peak on all-cause mortality. The effect of VO 2peak (L.min 1 and mL.kg 1 min 1 ) was examined individually in these analyses with and without adjustment for the following covariables: age, gender, and performance status (0 vs. 1, 2). VO 2peak was categorized into three groups for L.min 1 (<0.96 L.min 1 , 0.961.29 L.min 1 and >1.29 L.min 1 ) and mL.kg .1 min 1 (<13.9 mL.kg .1 min 1 , 14.017.3 mL.kg .1 min 1 , and >17.4 mL.kg .1 min 1 ). These categories were determined post-hoc via an unbiased tertile split of distributions of all patients. The median value of VO 2peak within each category was used as a predictor for linear trend in analyses. Survival time was defined as the time between registration and death; for patients remaining alive, survival was censored at the time of last known follow-up. Two sided p-values at the 0.05 level were used to determine statistical significance. All statistical analyses were performed using SAS Version 9.1.3 for Windows (SAS Institute, Cary, NC) by the CALGB statistical group. Graphics were performed using S-Plus version 8.0 for Windows.
To determine VO 2peak , an incremental, physician-supervised, cardiopulmonary exercise test (CPET) with 12-lead ECG monitoring was performed on an electronically-braked cycle ergometer with breath-by-breath expired gas analysis according to CPET guidelines for clinical populations. 5 , 10 All institutions used MedGraphics metabolic measurement systems with standardized electronic software. The exercise testing protocol was left to the discretion of the individual investigator. In general, however, preceding exercise, 3 minutes of resting metabolic data was collected before participants began cycling at 20W. Workloads were then increased 520W/min until volitional exhaustion or until a symptom-limitation was achieved. 5 Workload increments were determined by the medical history of the participant and at the discretion of the individual investigator. During exercise oxyhemoglobin saturation was monitored continuously using pulse oximetry (BCI, Hand-Held Pulse Oximeter, Waukesha, WN) while blood pressure was measured non-invasively by manual auscultatory sphygmomanometry every two minutes. Patients continued with usual medications on the day of testing. All data was recorded as the highest 30s peak VO 2 elicited during the CPET. Mean percentage of age and sex-predicted VO 2peak was calculated from the equations of Fitzgerald et al. 11 and Wilson and Tanaka 12 .
Full details regarding the study sample, recruitment and procedures have been reported previously. 9 In brief, study participants were enrolled in the Cancer and Leukemia Group B (CALGB) protocol . CALGB protocol was a prospective, multi-institutional study to assess the utility of VO 2peak for prediction of surgical risk including high risk patients with low FEV 1 . Patients with suspected stage IIIIA lung cancer, with or without preoperative histological confirmation, who were candidates for primary surgery with curative intent were eligible for study participation. Additional eligibility requirements included adequate laboratory values (hemoglobin, PaO 2 , hematocrit, potassium) and estimated survival >2 years. 9 Written informed consent was obtained from all participants prior to initiation of any study procedures.
The corresponding HRs for resected patients are also shown in Tables 2 and 3 . Compared with a peak VO 2 <0.96 L.min 1 , values of 0.961.29 L.min 1 and >1.29 L.min 1 were associated with a 34% and 41% reduction in the risk of all-cause mortality. The adjusted P for trend was 0.. The adjusted P for trend was non-significant (p trend =0.39) for relative VO 2peak (mL.kg. 1 min 1 ) ( Table 3 ). For non-resected patients, the HRs were 0.78 (95% CI, 0.34 to 1.79) and 0.43 (95% CI, 0.16 to 0.94) relative to the lowest VO 2peak (L.min 1 ) category (p trend =0.02) ( Table 2 ). The median length of survival from the time of exercise testing was 13.3 months for patients achieving a VO 2peak <0.96 L.min 1 relative to 16.1 months and 28.0 months for patients achieving a VO 2peak 0.961.29 L.min 1 and >1.29 L.min 1 , respectively. The corresponding HRs for relative VO 2peak (mL.kg. 1 min 1 ) were 0.34 (95% CI, 0.17 to 0.67) and 0.32 (95% CI, 0.14 to 0.71) relative to the lowest VO 2peak category (p trend =0.) ( Table 3 ; Figure 3 ). Results of all analyses were unchanged after excluding the 13 patients who died of surgical complications within 60 days of exercise testing.
Median follow-up was 30.8 months. During this period, 294 deaths were recorded (74% of the total sample). The median time from the cardiopulmonary exercise test to death was 3.7 years (95% CI: 3.0 to 4.5) and 1.4 years (95% CI: 1.0 to 1.7) among surgical patients and non-surgical patients, respectively. For the entire sample, mortality rates declined across increasing absolute (L.min 1 ) and relative (mL.kg. 1 min 1 ) VO 2peak categories (adjusted P trend = 0. and adjusted P trend = 0.08, respectively). Compared with patients achieving a VO 2peak <0.96 L.min 1 , the adjusted hazard ratio (HR) for all-cause mortality was 0.64 (95% CI, 0.46 to 0.88) for a VO 2peak of 0.961.29 L.min 1 and 0.56 (95% CI, 0.39 to 0.80) for a VO 2peak of >1.29 L.min 1 ( Table 2 ; Figure 1 ). The 5-year relative survival rate from the time of exercise testing was 28% for patients achieving a VO 2peak <0.96 L.min 1 relative to 32% and 39% for patients achieving a VO 2peak 0.961.29 L.min 1 and >1.29 L.min 1 , respectively. Compared with a peak VO 2 <13.9 mL.kg. 1 min 1 , (<3.9 METs) values of 14.017.3 mL.kg. 1 min 1 (4 METs to 4.9 METs) and >17.4 mL.kg. 1 min 1 (>5.0 METs) were associated with a 21% and 24% reduction in the risk of all-cause mortality ( Table 3 ; Figure 2 ).
The participant demographic and clinical characteristics are shown in Table 1 . Mean age was 64 ± 9 years, and 61% were male. For the total sample, 335 (84%) underwent surgical resection while 63 (16%) were deemed inappropriate for surgical resection at the determination of the attending thoracic surgeon. Thirteen patients died within 60 days of pulmonary resection. Overall, mean VO 2peak was 1.18 ± 0.42 L.min 1 and 15.8 ± 0.43 mL.kg 1 min 1 ; VO 2peak (mL.kg 1 min 1 ) was, on average, 36% below that for age and sex-matched normative data for sedentary individuals. FEV 1 , FEV 1 /FVC ratio, and D L CO was 1.9 ± 0.8L (70% of predicted), 84 ± 18%, and 15.8 ± 6.0 mL.mm/Hg.min (73% of predicted), respectively.
Our data demonstrate a strong and graded inverse association between VO2peak and all-cause mortality in patients with NSCLC. Compared with patients in the lowest VO2peak categories, higher VO2peak was associated with a statistically significant 21% to 24% reduction in the risk of mortality. These findings were consistent for age, gender, and performance status. The magnitude of risk reduction was even stronger for non-resected patients; in these patients, a VO2peak > 0.96 L.min1 or 13.9 mL.kg.1min1 was associated with a 24% to 61% reduction in the risk of mortality relative to the lowest VO2peak categories. Each 1.0 mL.kg.1min1 increase in VO2peak was associated with a 4% reduction in all-cause mortality.
The magnitude of risk reduction in the current study is similar to the prognostic value of VO2peak in patients with ischemic heart disease and chronic heart failure. For example, Kavanagh et al.13 reported that compared with a VO2peak <13 mL.kg.1min1 values of 13 mL.kg.1min1 were associated with a 50% and 29% reduction in the risk of cardiac mortality and all-cause mortality among >2,380 women referred for cardiac rehabilitation. Each 1.0 mL.kg.1min1 increase in VO2peak was associated with a 10% reduction in cardiac mortality. Similarly, Gitt et al.14 reported that a VO2peak <14 mL.kg.1min1 was associated with a 3-fold risk of death among 223 consecutive patients with heart failure. The strong prognostic value of VO2peak has been confirmed by several research groups.7, 8
The objective measurement of cardiorespiratory fitness using maximal (with direct or estimated assessment of VO2peak) or submaximal exercise testing for mortality prediction has not been exploited in the oncology setting. Several recent observational studies have provided the first evidence that self-reported physical activity (i.e., 918 MET-hrs.wk or 36hrs.wk of moderate paced walking) is associated with a ~30% to ~50% reduction in cancer-specific and all-cause mortality among early-stage breast and colorectal cancer patients.15, 16 However, given the stark limitations of self-report assessment of physical activity exposure, there are several methods available to clinicians and investigators that enable the objective determination of cardiorespiratory fitness in the oncology setting. The method should be determined by careful consideration of several factors including the purpose of the assessment (e.g., to determine exercise tolerance, prescribe exercise training, for cardiovascular diagnostics), the setting (e.g., hospital vs. community setting), and the cancer patient population (e.g., adjuvant vs. palliative care setting). These considerations have been reviewed in detail by our group elsewhere.5 In this study, we selected CPET because it provides the most accurate assessment of cardiorespiratory fitness and has been found to be a stronger predictor of prognosis than estimated methods of VO2peak.17 Despite the stark advantages of CPET, studies investigating the prognostic importance of submaximal testing (without gas exchange measurement) as well as functional capacity testing (e.g., six minute walk test) in lung and other solid malignancies are required. Such tests may be more appropriate in frail or elderly palliative patients, or when conducting a large number of tests in a non clinic-based setting. To this end, Kasymjanova et al.18 reported that six minute walk distance predicted prognosis in 45 patients with inoperable NSCLC.
The physiologic or molecular mechanisms underlying the association between VO2peak and mortality in NSCLC remain to be elucidated.19 In healthy populations, as well as those with CVD, the strong inverse relationship between cardiorespiratory fitness and CVD mortality is mediated by the association between high aerobic capacity (or exercise training-induced changes), established CVD risk factors, and possibly mitochondrial function.20 These pathways likely contribute, in part, to the graded mortality reduction observed in this study among resected patients as CVD is responsible for ~20%30% of deaths in this group.3 In addition, high aerobic capacity and/or exercise-induced improvements in VO2peak may also impact cancer-specific mortality via direct and/or indirect mechanisms.3 For direct mechanisms, several postulated biologic pathways have been proposed to underlie the relationship between exercise and cancer progression including modulation of circulating metabolic and sex-steroid hormone concentrations, immune surveillance, and systemic inflammation / oxidative damage.21 These pathways are centrally intertwined with the cardinal features of solid tumor progression. In contrast, higher VO2peak and/or chronic aerobic training is postulated to be associated with lower circulating concentrations of metabolic and sex steroid hormones, enhanced immunity, and lower inflammation / oxidative injury.21 These effects are thought to act in concert to inhibit tumor progression although scant direct or correlative evidence currently exists to support this notion.22
Indirect factors such as muscle wasting (atrophy) may also play a role. In this study, low absolute VO2peak was strongly associated with a higher risk of mortality among resected patients whereas a weak association was observed for relative VO2peak (adjusted for body mass) suggesting that other factors associated with body composition and/or muscle structure / function may be important in determining prognosis in NSCLC. Measures of skeletal muscle function, cross-sectional area, and whole-body composition (lean vs. body mass) are powerful predictors of mortality in non-cancer chronic diseases23 (e.g., heart failure, pulmonary disease, and renal failure), as well as other cancer populations2426 that, similar to NSCLC, experience a wasting syndrome. It is postulated that muscle and adipose tissue provide important energy reserves when exposed to a metabolic catabolic disease.27 The prognostic value of body composition / skeletal muscle function, in addition to cardiorespiratory fitness, in NSCLC is warranted.
Our findings may have implications for lung cancer mortality risk prediction and treatment. First, preoperative VO2peak is a well-established risk stratification tool to determine surgical complication risk2831 and, on the basis on our findings, may have utility for long-term mortality prediction. VO2peak may provide an unbiased assessment of physical performance not permitted by current subjective PS scoring systems which may, in turn, provide more accurate prognostication and personalized care. To this end, our findings suggest that a VO2peak of <14 mL.kg.1min1 (determined from unbiased tertile data segregation) may identify patients with poor prognosis although confirmation is required. Other physiological objective measures, other than cardiorespiratory fitness testing, such as FEV1 may also be prognostic. In ancillary analyses, we found that mortality rates declined significantly across increasing absolute FEV1 (Ptrend= 0.) although FEV1 became non-significant with the addition of VO2peak in the multivariate model (analysis not presented). These preliminary results suggest that it is critically important to consider the integrative capacity of all organ components involved in O2 transport (as measured by VO2peak), as opposed to one component (such as lung function), when performing mortality risk prediction.
Second, our findings indicate that VO2peak may be an attractive therapeutic target to improve clinical outcome in NSCLC. Numerous reports have provided unequivocal evidence that aerobic training is associated with a 15% to 20% improvement in VO2peak32 in 1215 weeks while changes in cardiorespiratory fitness are associated with substantial reductions in cardiovascular mortality irrespective of baseline fitness.33 Few studies have investigated the role of exercise training in NSCLC.34 Our group recently completed two pilot studies investigating the feasibility, safety, and preliminary efficacy of high-intensity supervised aerobic training on peak VO2peak among NSCLC patients in the preoperative (46 weeks of training)35 and postoperative (14 weeks of training)36 setting. VO2peak increased 2.4 mL.kg.1min1 (14.6%) and 1.7 mL.kg.1min1 (11%) and preoperative and postoperative setting, respectively.35, 36 Based on the findings of this study, these improvements would potentially translate into a ~10% and ~7% improvement in overall survival. In comparison, adjuvant chemotherapy is associated with an absolute 5.3% improvement in survival over 5 years.37 This preliminary data provide proof of principle that a supervised aerobic training is safe and well-tolerated among operable NSCLC patients. On the basis of this data, our group is conducting an ongoing trial investigating the optimal type of exercise training to improve VO2peak in post-surgical NSCLC patients as well as change in the physiological mechanisms (i.e., organ components involved in O2 transport) that govern VO2peak.38
This study had several limitations. We only had information on death from any cause; the specific cause of death is not known. We also do not have information on disease recurrence and progression, disease stage or type and dose of any anticancer therapy (e.g., locoregional radiotherapy, chemotherapy, etc.), and the reasons for surgical ineligibility. Thus, analyses were not adjusted for these important covariates. Also patient selection bias may exist because of exclusion of patients deemed physically unable to perform exercise testing.
VO2peak is a strong independent predictor of survival in NSCLC that may complement traditional markers of prognosis to improve risk stratification and prognostication. Our findings further indicate that exercise training and/or other therapeutic strategies that augment VO2peak may hold considerable promise for improving prognosis in patients with NSCLC.
What is a PSA test normal range? What is a dangerous PSA level?
When you or a loved one receive a PSA score, some of the first questions that come to mind are, Is this normal? and What now? Do I need to take action?
The answers to those questions depend on your age and a few other factors. Youll find a normal PSA ranges by age calculator below, as well as a table listing them out. Weve also provided information to help you understand what the range means.
P
rostate-S
pecificA
ntigenThe prostate is a walnut-sized gland found between the bladder and the rectum in males. Its primary job is to produce seminal fluid. The prostate creates a protein, the prostate-specific antigen, or PSA. A PSA screening test is a blood test approved by the FDA in to measure the levels of PSA in a mans blood.
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Small amounts of PSA ordinarily circulate in the bloodstream and can be measured by a PSA test to monitor the health of the prostate. This test is intended to screen for prostate cancer, find other prostate-related conditions, or monitor PSA levels in those in treatment for prostate cancer. This is a simple blood test which reports PSA levels as nanograms of PSA per milliliter (ng/mL) of blood.
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Please enter a number from 1 to 125.
Enter your PSA score (measured in ng/mL)Please enter a number greater than or equal to 0.
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Colloquially, prostate cancer screening is thought to be routinely undertaken by men over the age of 40. The American Urological Association recommends the following:
It is important to note that PSA levels can rise naturally with age, and that a number of benign (not cancerous) conditions can also affect PSA levels, such as prostatitis (inflammation of the prostate), benign prostatic hyperplasia (BPH, enlarged prostate), urinary tract infection (UTI), or even injury to the prostate.
Other factors such as sexual activity right before testing, certain exercises, or even diet can impact the PSA levels as well. It is essential to consult a doctor regarding the meaning and next steps of your PSA testing results.
What is a normal PSA level? What is a dangerous PSA level?
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What is a normal PSA level by age? We mentioned earlier in this article that PSA levels increase with age due to age related growth of the prostate gland. A doctor will therefore take into account an age-adjusted PSA level when discussing your prostate health:
Age Range (years) Baseline Age-Adjusted PSA Levels ng/mL 40 to 49 0 to 2.5 50 to 59 0 to 3.560 to 69
0 to 4.5
70 0 to 6.5
Although there are normal PSA levels by age range, it is still important to screen routinely (as instructed by your doctor) to ensure these normal levels are not rising.
In the past, many doctors wanted men with elevated PSA and/or an abnormal digital rectal examination to undergo a prostate biopsy. Today, this is not a course of action recommended by the American Urological Association. In such cases, multiparametric prostate MRI (mpMRI) is now recommended as the best front-line test to detector rule outprostate cancer.
If a mpMRI shows a suspicious finding, a MRI-guided biopsy is the most accurate way to perform a biopsy of the prostate. If this is not possible, an MRI can be used with an ultrasound-guided biopsy. This is referred to as a fusion biopsy, and is more accurate than an ultrasound biopsy alone.
PSA level (ng/mL) 0 to 2.0 2.0 to 4.0 4.0 to 10.0 Greater than 10.0 Prostate Cancer on biopsy (%) 10% 25% 17%-32% 43-65%
Consult with your general practitioner or urologist about receiving a PSA test in their offices. PSA tests are typically covered without co-pay or deductible by Medicare once a year for men 50 years and older. Many states now have laws which require private health insurers to cover the costs for PSA testing. However, additional PSA test costs may need to be covered by the patient.
For those without insurance, or for those with insurance that does not cover PSA testing, free tools are available through advocacy groups, such as ZERO.
ZERO National Free Testing Map
Companies such as imawaretm also offer in-home PSA testing kits and telemedicine appointments to discuss your PSA test results with a licensed physician. All imaware test kits are easy to use. After registering the test kit online, results will populate in the secure patient portal within 5-7 business days. You can submit your receipt of this test to insurance for potential reimbursement.
At-Home testing is now at a point where results can be provided accurately and quickly within 5 business days, with real physicians providing telemedicine support through the entire testing process
Dr. Diamandis Lunenfeld-Tanenbaum Research Institute, Sinai Health System
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